Experiments are proposed to elucidate the mechanism of the biosynthesis of presqualene pyrophosphate by the use of stereospecifically labelled farnesyl pyrophosphates. Continue work on the elucidation of the shunt (the trans- methylglutaconate shunt) of intermediates of sterol biosynthesis, starting probably by the hydrolysis of 3,3-dimethylallyl pyrophosphate, which was discovered recently in the P.I.'s laboratory. Examine the existence of the shunt in man by the use of (C13)-labelled mevalonates. Develop new inhibitors of prenyl transferase which might be effective in vivo for the inhibition of cholesterol biosynthesis. The discovery of the transmethylglutaconate shunt offers a rational basis for making specific inhibitors of cholesterol biosynthesis. Acetylenic compounds and oxime esters are proposed in the first instance. Continue work with human leukocytes as monitors of control of lipid biosynthesis in man. A general hypothesis based on current work is proposed as an explanation of some of the hypercholesterolemias which can be tested with human leukocytes.